Synthesis and Quantum Chemical Calculation of Benzamide Derivatives Containing Capsaicin and Their Bacteriostatic and Antifouling Properties

JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Article

Synthesis and Quantum Chemical Calculation of Benzamide Derivatives Containing

Capsaicin and Their Bacteriostatic and Antifouling Properties

Gang Wu, Xiaohui Jiang, Liangmin Yu*, Shuwei Xia and Xiaolin Yu

Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, Ocean University of China,

Qingdao 266100, P. R. China

(Received: Jan. 28, 2015; Accepted: Aug. 25, 2015; Published Online: Sept. 18, 2015; DOI: 10.1002/jccs.201500037)

Thirteen benzamide derivatives containing capsaicin (BDCCs) have been successfully synthesized via the

current method (Friedel-Crafts alkylation reaction). The resultant monomers were characterized by IR, ¹H

and ¹³C NMR, elemental analysis and HRMS. Characterization results were in agreement with the pro-

posed structures of the products. Quantum chemistry calculation yielded three parameters, namely, De_L-H

,

HF values (total energy) and dipole that could explain activity, stability and polarity respectively, and the

relationship of each parameter with antimicrobial and antifouling performance was also preliminary dis-

cussed. The bacteriostatic property of the 13 compounds was evaluated by minimum inhibitory concentra-

tion (MIC) and bacteriostatic ring tests. Experimental results indicated that these compounds can inhibit

Staphylococcus aureus and Escherichia coli. The antifouling effectiveness of the novel antifoulants was

investigated using panel tests at the eighth harbor, Qingdao. Four-month exposure results were compared.

The compounds exhibited better antifouling properties than the blank panel without antifouling coating or

the panel with a common coating. However, test panels with the antifouling coatings were covered with

trace amounts of algae and Balanus because of weakening of antifouling ability over extended periods of

time. All results demonstrate that the new compounds synthesized via our method can be applied in envi-

ronment-friendly antifouling paints.

Keywords: Benzamide derivatives; Capsaicin; Quantum chemistry; Bacterium-inhibition;

Antifouling property.

INTRODUCTION

shown to cause maldevelopment, reproductive failure, gen-

der-bending and sterility of various marine species.⁸Fur-

thermore, studies in coastal waters indicate that TBT accu-

mulates in the marine food chain, thereby leading to abnor-

mal growth in various organisms. As the harm posed by

TBT to the marine environment and its severe impact on

this ecosystem have become better understood, the United

Nations (UN) International Maritime Organization (IMO)

decided that coatings containing TBT must be eliminated

in vessels less than 25 m long by January 1, 2008.⁹Thus,

development of a new environment-friendly antifoulant is

biodegradable¹⁰and harmless to humans and non-target or-

ganisms is an urgent necessity.

So far, the most successful mean to prevent the

growth of fouling organisms is utilizing antifouling paints

which are attached on the hulls of boats and other sub-

merged static structures. These paints are applied because

accumulation of fouling organisms increases the frictional

resistance of a boat moving through water, thereby result-

ing in lower speed, greater fuel consumption and poorer

maneuverability. Moreover, fouling organisms on static

structures will reduce stability and conceal structural de-

fects, and consequently cause the safety issues.^1,2

Considering that antifouling agents are important

components of antifouling coatings, tributyltin (TBT)³

(Fig. 1) systems earned acclaim in the 1970s as the most ef-

fective antifoulant ever developed. TBT is highly effective,

provides antifouling properties for five or more years, and

maintains the smoothness and low resistance of the boat

bottom. Antifouling issues appear to be resolved eventu-

ally by this coating. However, TBT presents several ad-

verse effects on the environment;^4-7the coating has been

Capsaicin, which is extracted from chili and other

pepper fruits and has a pungent odor (Fig. 2), was recently

identified as an effective non-toxic antibacterial and anti-

fouling alternative;^11-13thus, applicability of this com-

pound in relevant applications has exerted increased re-

search attention.

Despite its promising properties, capsaicin extraction

* Corresponding author. Tel: +86 532 66781845; Fax: +86 532 66781845; Email: Yuyan@ouc.edu.cn

Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500037

J. Chin. Chem. Soc. 2015, 62, 861-870

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Wu et al.

sults exhibit no imaginary frequency and determine the sta-

ble configurations. We identified the stable structures of

the BDCCs and calculated the following parameters: the

highest occupied orbital energy (e_H), the lowest empty or-

bital energy (e_L), the difference between the lowest empty

and highest occupied orbital energies (De_L-H), HF value

and dipole. Our findings provide a theoretical basis for

further experiments. The calculation results are shown in

Table 1.

As can be seen from the contrast of the size of the pa-

rameters which were products and the corresponding raw

materials, N-methylbenzamide grafted on the benzene ring

with different functional groups, which exerted a big influ-

ence on De_L-H, HF and dipole values of the compounds (see

Table 1).

Fig. 1. Structure of TBT.

The smaller the De_L-H, the greater the activity of the

compound and the more unstable it is. Results show that the

relative stability of the 13 BDCCs follows the order 1f > 1e

> 1m > 1b > 1l > 1k > 1a > 1j > 1i > 1h > 1d > 1c > 1g. For

isomers, a lower HF value corresponds to better stability of

the compound. The order of 1l and 1m, which are isomers

is 1m_HF> 1l_HF, so 1l possesses better stability than 1m. Ac-

cording to the relationship between the polarity and sol-

vent, the larger the dipole value, the greater the polarity and

the easier a compound may be dissolved in a polar solvent.

Results show that the polarity of the BDCCs follows the or-

der 1h > 1j > 1m > 1k > 1e > 1d > 1f > 1b > 1c > 1a > 1g >

1i > 1l.

Fig. 2. Structure of capsaicin.

and synthesis are not very feasible because of low yields

and high costs, both of which limit its suitability for use as

an ideal antifoulant. Recent research has focused on ca-

psaicin analogs, which have been reported to exhibit signif-

icant biological activity and are widely used as antifoulants

because of their antibacterial and chemical stability proper-

ties. This work discusses antifouling paints, with particular

emphasis on capsaicin analogs generated by Friedel-Crafts

alkylation using an acid as a catalyst;^14,15this technique can

overcome the difficulties of capsaicin extraction. In this

study, 13 new capsaicin analogs with good antimicrobial

and antifouling properties were obtained. Testing further

revealed that the effectiveness of these compounds coin-

cides with their De_L-Hand dipoles determined through

quantum chemistry calculation.

With regard to De_L-H, as can be seen 1(x)_DeL-H

<

2(x)_DeL-H(x = b, c, d, e, f, g, h, i, j, k, l, m) from the Table 1,

except 1a > 2a, the reactivity of the products is superior to

those of the raw materials. For 1a, the hydroxyl portion of

the compound increases, but this result may be due to

N-methylbenzamide substitution at the hydrogen of the

benzene ring, which weakens the structural activity of the

compound overall. The low activity of the BDCCs and

their pungent odor indicate excellent performance as anti-

RESULTS AND DISCUSSION

bacterial and antifouling coatings. In regard to HF, 1(x)_HF>

Quantitative structure and activity relationship

Using Chemoffice software to build compound mo-

lecular models, the geometric structures may be optimized

by applying density functional theory at the B3LYP/6-31G

(d, p) level according to closed shell singlets and prelimi-

narily discussed the relationship of the three parameters

(De_L-H, HF (total energy) and dipole) and their correspond-

ing activity, stability and polarity. Based on configuration

optimization calculations of vibration frequency, the re-

2(x)_HF(x = a, b, c, d, e, f, g, h, i, j, k, l, m), the energy of the

BDCCs are higher than those of the raw materials because

the space volume of the products is fairly large, which in-

creases their instability. For dipole, 1(x)_dipole> 2(x)_dipole(x =

b, c, d, e, f, g, h, i, j, k, l, m), larger dipoles correspond to

greater polarity. With the exception of 1a < 2a, the polari-

ties of the other BDCCs are greater than those of the raw

materials. Thus, when the 13 BDCCs are incorporated as

antifoulants into paint, they are expected to show good sol-

862

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J. Chin. Chem. Soc. 2015, 62, 861-870

JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Capsaicin Derivatives: Calculation, Antifouling

Table 1. Parameters of monomers containing capsaicin (1x on behalf of 13 BDCCs, 2x on

behalf of the corresponding raw materials, x = a, b, c, d, e, f, g, h, i, j, k, l, m)

Compounds

e_H/eV

e_L/ eV

De_L-H/eV

HF/hartree

Dipole/D

1a

2a

1b

2b

1c

2c

1d

2d

1e

2e

1f

-0.23792

-0.23519

-0.21085

-0.20978

-0.19632

-0.19394

-0.22992

-0.23685

-0.22407

-0.22899

-0.25735

-0.26779

-0.20203

-0.20829

-0.22703

-0.23365

-0.20846

-0.21118

-0.22171

-0.23137

-0.23551

-0.23905

-0.21352

-0.21212

-0.21772

-0.21090

-0.06138

-0.05884

-0.03094

0.00848

-0.03713

-0.03350

-0.06977

-0.07087

-0.03655

-0.03905

-0.06153

-0.06337

-0.04844

0.00526

-0.06081

-0.03704

-0.03803

0.00700

-0.05009

-0.00269

-0.05844

-0.05341

-0.03620

0.00815

-0.03144

0.00712

0.17654

0.17635

0.17991

0.21826

0.15919

0.16044

0.16015

0.16598

0.18752

0.18994

0.19582

0.20442

0.15359

0.20303

0.16622

0.19661

0.17043

0.21818

0.17162

0.22868

0.17707

0.18564

0.17732

0.22027

0.18628

0.21802

-1011.33972712

-572.25945269

-1061.07286897

-622.00140574

-1033.97585319

-594.89841992

-901.39196612

-462.31293712

-974.44416020

-535.37034951

-1223.16761018

-784.08969684

-943.13291013

-504.06234886

-2040.49730879

-1162.32827916

-1339.45158627

-461.30075280

-1380.79441123

-502.63401022

-1298.96616820

-420.80528750

-1264.25573296

-386.10396522

-1264.27263405

-386.11939514

3.7974

4.5386

4.2572

1.9287

4.1616

1.9410

5.6437

4.0072

6.3830

3.2871

5.6332

5.2036

3.6328

1.2742

11.7284

5.6249

2.9959

2.1925

8.0892

0.0962

6.9535

4.5376

2.7733

0.9680

7.1437

1.3606

2f

1g

2g

1h

2h

1i

2i

1j

2j

1k

2k

1l

2l

1m

2m

ubility in the solvent. As such, obtaining more uniform and

effective antifouling paints is feasible.

Equilibrium configuration

Compound is obtained by calculating the most stable

structure, and their spatial configurations as shown in Fig.

3, the gray on behalf of the C atom, white represents H

atom, red represents O atom, blue represents N atom, yel-

low represents S atom.

Evaluation of antimicrobial activity of the BDCCs

MIC of the BDCCs

The lowest concentration, which shows no growth of

tested organism after macroscopic evaluation, was deter-

mined as the MIC.¹⁶Fig. 4 presents the MIC values of the

13 BDCCs against Sa and Ec.

The 13 BDCCs showed excellent antimicrobial activ-

ity toward Ec and Sa (Fig. 4). Except for 1b, the MICs of

the BDCC against Sa is equal to or less than that of natural

capsaicin, which illustrates that these 12 BDCCs show an-

tibacterial properties similar to or better than that of natural

capsaicin. The poor inhibitory performance of 1b may be

attributed to its structure, which contains two tert-butyls

Fig. 3. Stable structure of monomers containing cap-

saicin.

and is sterically hindered. Thus, it is difficult to play bac-

teriostatic effect through the mechanism of bacterial bio-

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compounds present good antimicrobial activity, especially

1a, 1f, and 1l (see Table 2). However, the antimicrobial ac-

tivities of 1b, 1i, and 1g are slightly poorer than those of

others. Results of the analysis are consistent with our MIC

findings.

Result of test panels in seawater

Biocide additives are commonly used to prolong the

life of surface coatings. These additives prevent or slow the

growth of organisms on the coating surface. Without bio-

cide additives, biological species adhere to the coating sur-

face, which can eventually lead to disbonding and blister-

ing of coatings under various service conditions. The

BDCCs were incorporated into paint coatings, and an ex-

periment was performed at sea for 120 d, from June 2014 to

September 2014, which is the period of vigorous growth of

marine organisms (including marine algae, Enteromorpha,

and barnacles). The results are shown in Fig. 6.

Fig. 4. MIC of thirteen tested compounds and cap-

saicin.

logical structures destroyed.¹⁷

The MICs of all of the BDCCs except 1a against Ec

are slightly larger than or equal to that of natural capsaicin,

which indicates that they have relatively weak antibacterial

properties. The improved antibacterial property of 1a may

be attributed to its heterocyclic structure, which endows the

compound with a variety of biological activities and pre-

sents remarkable medicinal value and potential chemo-

therapeutic properties.¹⁸These advantages render 1a with

good activity against the two bacteria. Coupled with the

compound containing a hydroxyl bond causes overall ac-

tivity to increase, which easily exerts a bacteriostatic effect

by destroying the bacterial biological structure.

Macrofouling organisms, algae and microbial film,

barnacles, and mussels are important marine organisms,

and settlement of macrofouling organisms is based on for-

mation of biofilms. We investigated the antifouling proper-

ties of the 13 new compounds by taking photographs of the

test panels with surface attachment of marine organisms.

Biofouling is generally recognized to undergo two

important stages.¹⁹The initial stage is formation of biologi-

cal mucosa. Biological mucosa which is dominated by uni-

form particles of bacteria and diatoms forms on the surface

of the immerged object. In certain antifouling coatings, this

film presents stratified layers, which are divided into the

bacterial and diatomic layers, and it sets the scene for later

events.²⁰The final stage of biofouling involves macro-

As can be seen qualitatively, the quality of antibacte-

rial properties is consistent with the De_L-Hvalue and dipole

of the quantum chemistry calculation, except for a few ex-

ceptions (see Fig. 4). Smaller De_L-Hvalues of the com-

pounds translate to greater activity and higher instability.

More unstable compounds may lead to greater MIC, indi-

cating poorer inhibition. From the perspective of the polar-

ity of compounds, greater polarity indicates stronger hy-

drophilicity, and weaker hydrophobicity indicates weaker

cell wall and cell membrane permeability. Therefore,

greater polarities indicate poorer antibacterial activity.

Bacteriostatic ring results

Biocide additives were prepared in vitro to determine

their microbial activity against Sa and Ec using the disc dif-

fusion method (see Fig. 5). Table 2 reveals that the BDCCs

show strong inhibitory effects against the tested bacteria,

although 1b presented inhibitory effects against Sa only.

Each experiment was performed in triplicate, and the aver-

age value of three measurements was obtained. The diame-

ters of bacteriostatic ring are shown in Table 2 (outer diam-

eter of Oxford cup, 8 mm).

Fig. 5. Anti-microbial test specimens 1®1a, 2®1i,

3®1b, 4®1j, 5®1c, 6®1h, 7®1k, 8®1d,

9®1e, 10®1f, 11®1g, 12®1l, 13®1m, O®

acetone without tested compounds.

Table 2. The diameter of bacteriostatic rings

Compounds 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m O

Sa/mm

Ec/mm

14 10 10 12 13 13 10 11 10 10 12 13 12 8

14 11 11 12 14 10 12 10 11 13 13 13 8

The diameters of the bacteriostatic ring are directly

proportional to antimicrobial activity. All of the tested

9

864

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JOURNAL OF THE CHINESE

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Capsaicin Derivatives: Calculation, Antifouling

Fig. 6. Results of testing panels in the sea. Panel No.: (1a) 1343; (1b) 1344; (1c) 1345; (1d) 1346; (1e) 1347; (1f) 1348; (1g)

1349; (1h) 1350; (1i) 1351; (1j) 1352; (1k) 1353; (1l) 1354; (1m) 1355; (1n) 1342 the coating without capsaicin de-

rivatives; (1o) blank.

organism accumulation. Spores of algae, marine fungi, and

ciliate protozoa appear on the biofilm, and a more complex

community is formed; these communities initiate settle-

ment of other macroorganisms, such as mussels, barnacles,

bryozoans, tubeworms, and algal growth.

1347 and 1355 were washed off by seawater. Most panels

evidently exhibited biological mucosa and barnacles in

comparison with the panels at 60 d, which indicates weak-

ening of antifouling performance. More barnacles were

found and attachment of barnacles occurred on the basis of

biofilm on the panels. Panel 1348 showed some biofilm

and barnacle formation. Panels 1343 to 1355 exhibited a

certain degree of antifouling property, especially panels

1348, 1347, 1355, and 1354; these results indicate superior

antifouling property in comparison with other panels.

We note that antifouling paints exhibiting BDCCs

showed performance consistent with the De_L-Hand dipole

values of the experimental compounds with certain excep-

tions. Higher De_L-Hvalues translate to lower activity of the

compounds and better stability. Thus, the antifouling paints

possess fairly long antifouling effect.

The blank panel was covered with various biofilms

and substantial green marine algae such as Enteromorpha

prolifera (Fig. 6). No marine organisms were attached to

the other panels at 30 day, except for panel 1342, which

showed trace amounts of microbial mucosa. This result

suggests that BDCCs as antifoulants can improve the

antifouling properties of paint coatings. After 60 d, except

for 1346 and 1345, which showed a small amount of algae

and biofilms, other panels basically presented no microbial

attachment. By contrast, 1342 and the blank panel showed

small amounts of micro-organism mucosa and barnacles

instead of E. prolifera; likely because of the unstable at-

tachment of the bacteria to the panel. All other panels

showed mud and a small quantity of microfilms. After 90 d,

1353, 1352, 1351, 1350, and 1349 also showed trace

amounts of barnacle attachment; 1348, 1355, 1344, 1342,

and the blank panel showed more attachment. Panel 1348

presented the best effect among the tested panels. Over a

period of 120 d, certain biofilms and sludge in panels 1348,

Adding BDCCs to paint can significantly improve

antifouling performance, especially at the most vigorous

period of barnacle growth. This study presents a new

method for the future development of environment-

friendly antifouling paints.

EXPERIMENTAL

General materials: 4-Hydroxycoumarin, 1,2-dimethoxy-

J. Chin. Chem. Soc. 2015, 62, 861-870

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Wu et al.

benzene, 2,6-di-tert-butylphenol, diphenylmethane, 2-phenyl-

indole, 4,4’-sulfonyldiphenol, p-hydroxybenzaldehyde, benzal-

acetone, 4-methylsalicylic acid, 2-chlorobenzonitrile, 2-tert-

butyl-4-methylphenol, 3-methylanisole, 2,5-dimethylphenol, and

N-(hydroxymethyl)benzamide were purchased from Aladdin or

local companies. All solvents used in the experiments were at

least of reagent grade administered without further purification.

Synthesis of 13 BDCCs: Thirteen compounds were syn-

thesized by Friedel-Crafts alkylation,^21,22which requires Lewis

and proton acids as catalysts. Taking 1a as an example, (35.4 g,

0.2 mol) of N-(hydroxymethyl)benzamide, (16.2 g, 0.1 mol) of

4-hydroxycoumarin, and (50 mL) absolute ethanol were added to

a 250 mL three-necked round-bottom flask in a heating water bath

(35 °C) and then stirred. Concentrated sulfuric acid was then

added to this solution in drops (reaction time: 5 d). The resultant

white precipitate was recrystallized in ethanol and then dried un-

der vacuum to obtain a white powder.

Hz, 1H, NH), 8.877 (s, 1H, OH); ¹³C NMR (150.9 MHz, DMSO-

d₄): d = 166.61, 153.16, 139.53, 135.16, 131.55, 130.96, 128.77,

127.64, 124.15, 43.35, 34.94, 30.82; HRMS, m/z: 340.2282

([M+H]⁺), 362.2103 ([M+Na]⁺); EA, C₂₂H₂₉NO₂: 339.4711,

found (calculated) C: 77.82% (77.84%), H: 8.38% (8.61%), N:

4.30%(4.13%).

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1b.

N-[(2-phenyl-1H-indol-4-yl) methyl]benzamide (1c): red

powder, yield 88.9%. m. p.: 225.9-226.8 °C. IR (KBr):/cm^–1: u_C-C

= 696.54, u_C=C= 1449.46, u_CO-N= 1638.46, u_C-N= 3402.83; ¹H

NMR (DMSO-d₆, 600 MHz), d (ppm): 1.321 (d, J = 6.0 Hz, 2H,

CH₂), 4.310 (s, 1H, CCHC), 6.322 (d, J = 7.2 Hz, 2H, PhH), 7.403

(t, J = 5.4 Hz, 12H, PhH), 7.957 (t, J = 1.2 Hz, 1H, NH), 11.027 (s,

1H, NH); ¹³C NMR (150.9 MHz, DMSO-d₄): d = 167.56, 165.02,

151.22, 148.58, 138.35, 132.07, 130.49, 127.73, 126.85, 125.63,

123.79, 110.67, 56.65, 35.95, 35.29, 35.15, 29.94; HRMS, m/z:

349.1300 ([M+Na]⁺); EA, C₂₂H₁₈N₂O: 326.3911, found (calcu-

lated) C: 80.72% (80.96%), H: 5.43% (5.56%), N: 8.48%

(8.58%).

Characterization studies: The resultant monomers were

1

characterized by H and ¹³C NMR, HRMS, IR, and elemental

analysis. Thirteen benzamide derivatives containing capsaicin

(BDCCs), which are respectively denoted as 1a, 1b, 1c, 1d, 1e, 1f,

1g, 1h, 1i, 1j, 1k, 1l, and 1m (Fig. 7), were synthesized in our lab-

oratory.

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1c.

N-[(4-hydroxy-2-oxo-2H-chromen-8-yl)methyl]benzamid

e (1a): white powder, yield: 83.3%, m.p. 221.8~222.6 °C. IR

(KBr):/cm^–1: u_C-C= 755.19, u_CH2= 1563.20, u_C=C= 1624.32,

u_CO-N= 1678.56, u_=CH= 3062.76, u_OH= 3330.05; ¹HNMR

(DMSO-d₆, 600 MHz), d(ppm): 4.403 (d, J = 5.4 Hz, 2H, CH₂),

7.399 (d, J = 6.0 Hz, 2H, PhH), 7.511 (t, J = 8.0 Hz, 2H, PhH),

7.602 (t, J = 7.4 Hz, 1H, PhH), 7.643 (s, 1H, HOCCHCO), 7.971

(d, J = 5.9 Hz, 3H, PhH), 9.859 (t, J = 5.9 Hz, 1H, NH), 13.154 (s,

1H, OH); ¹³C NMR (150.9 MHz, DMSO-d₄): d = 170.05, 164.06,

163.16, 152.93, 133.17, 132.76, 132.51, 128.98, 128.18, 124.63,

124.21, 116.67, 116.62, 102.39, 34.98; HRMS, m/z: 296.0909

([M+H]⁺), 318.0733 ([M+Na]⁺); Elemental analysis (EA),

C₁₇H₁₃NO₄: 295.2894, found(calculated), C:68.95%(69.15%),

H:4.14% (4.44%), N: 5.00%(4.74%).

N-{4-[(1Z)-3-oxobut-1-en-1-yl] benzyl}benzamide (1d):

brown powder, yield 45.9%. m. p.: 154.8-156.0 °C. IR (KBr):

/cm^–1: u_C-C= 696.12, u_C=O= 1529.36, u_CO-N= 1636.92, u_=CH

=

1

3058.83, u_OH= 3440.49; H NMR (DMSO-d₆, 600 MHz), d

(ppm): 4.882 (d, J = 5.4 Hz, 2H,CH₂), 5.237 (s, 3H, CH₃), 7.551

(d, J = 5.4 Hz, 8H, PhH), 7.924 (t, J = 7.2 Hz, 3H, PhH), 9.057 (t, J

= 5.9 Hz, 1H, NH); ¹³C NMR (150.9 MHz, DMSO-d₄): d =

166.92, 134.42, 131.87, 129.73, 128.72, 127.89, 45.64; HRMS,

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1a.

N-[(4-hydroxy-3, 5-di-tert-butyl) methyl)]benzamide (1b):

white powder, yield 76.5%. m. p.: 195.3-196.0 °C. IR (KBr):

/cm^–1: u_C-C= 715.50, u_CH2= 1539.55, u_CO-N= 1635.76, u_C-H

=

1

2961.05, u_OH= 3634.30; H NMR (DMSO-d₆, 600 MHz), d

(ppm): 1.324 (s, 18H, C(CH₃)₃), 4.337 (d, J = 6.0 Hz , 2H, CH₂),

6.791 (s, 1H, PhH), 7.044 (d, J = 5.4 Hz, 2H, PhH), 7.427 (t, J =

6.0 Hz, 2H, PhH), 7.827 (d, J = 7.2 Hz, 2H, PhH), 7.839 (t, J = 5.9

Fig. 7. Structures of 13 BDCCs.

866

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J. Chin. Chem. Soc. 2015, 62, 861-870

JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Capsaicin Derivatives: Calculation, Antifouling

m/z: 280.1335 ([M+H]⁺), 302.1157 ([M+Na]⁺); EA, C₁₈H₁₇NO₂:

279.3330, found (calculated) C: 77.71% (77.40%), H: 5.82%

(6.13%), N: 5.39% (5.01%).

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1d.

EA, C₁₉H₂₃NO₂: 297.3914, found (calculated) C: 76.88%

(76.73%), H: 7.71% (7.80%), N: 4.88% (4.71%).

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1g.

N-{2-hydroxy-3-methylbenzamide-5-[(4-hydroxyphenyl)

sulfonyl]benzyl}benzamide (1h): yellow powder, yield 29.6%.

N-(2-methyl-4-hydroxyl-5-carboxyl)benzamide (1e):

white powder, yield 59.7%. m. p.: 135.6-136.2 °C. IR (KBr):

m. p.: 131.6-132.9 °C. IR (KBr):/cm^–1: u_C-C= 693.73, u_S=O

=

/cm^–1: u_C-C= 694.26, u_CH3= 1286.57, u_COOH= 1527.48, u_CO-N

=

1286.73, u_CO-N= 1635.86, u_OH= 3308.95; ¹H NMR (DMSO-d₆,

600 MHz), d (ppm): 4.872 (d, J = 6.0 Hz, 2H, CH₂), 5.675 (d, J =

3.3 Hz, 4H, PhH), 6.903 (d, J = 9.0 Hz, 2H, PhH), 7.468 (t, J = 7.8

Hz, 4H, PhH), 7.526 (d, J = 7.8 Hz, 2H, PhH), 7. 630 (s, 2H, PhH),

7.878 (t, J = 7.2 Hz, 4H, PhH), 7.899 (t, J = 5.9 Hz, 2H, NH),

9.038 (s, 2H,OH); ¹³C NMR (150.9 MHz, DMSO-d₄): d = 166.94,

162.06, 134.41, 132.55, 131.88, 129.81, 128.73, 127.89, 116.42,

45.66; HRMS, m/z: 517.1433 ([M+H]⁺), 539.1258 ([M+Na]⁺);

EA, C₂₈H₂₄N₂O₆S: 516.5649, found (calculated) C: 65.29%

(65.10%), H: 4.68% (4.68%), N: 5.08% (5.42%).

1

1635.30, u_OH= 3307.23; H NMR (DMSO-d₆, 600 MHz), d

(ppm): 2.338 (d, J = 2.7 Hz, 2H, CH₂), 3.831 (s, 3H, CH₃), 6.870

(s, 1H, PhH), 7.473 (t, J = 7.8 Hz, 3H, PhH), 7.544 (d, J = 7.2Hz,

2H, PhH), 7.644 (t, J = 6.0Hz, 1H, PhH), 7.690 (t, J = 7.8 Hz, 1H,

NH), 7.913 (s, 1H, OH), 9.041 (s, 1H, COOH); ¹³C NMR (150.9

MHz, DMSO-d₄): d = 166.92, 134.42, 131.87, 128.72, 127.89,

127.71, 120.81, 117.64, 45.64; HRMS, m/z: 286.1077 ([M+H]⁺),

308.0898 ([M+Na]⁺); EA, C₁₆H₁₅NO₄: 285.2946, found (calcu-

lated) C: 67.08% (67.36%), H: 5.63% (5.30%), N: 4.97%

(4.91%).

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1h.

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1e.

N-(2-methylbenzamide-4, 5-dimethoxybenzyl)benzamide

(1i): white powder, yield 59.8%. m. p.: 192.7-193.3 °C. IR

(KBr):/cm^–1: u_C-C= 692.35, u_CH3-O= 1274.54, u_CO-N= 1627.92;

¹H NMR (DMSO-d₆, 600 MHz), d (ppm): 3.699 (s, 6H, OCH₃),

4.532 (d, J = 5.4 Hz, 4H, CH₂), 6.952 (s, 2H, PhH), 7.464 (t, J =

7.2 Hz, 4H, PhH), 7.517 (d, J = 6.0 Hz, 2H, PhH), 7. 884 (t, J = 7.2

Hz, 4H, PhH), 8.938 (t, J = 5.4 Hz, 2H, NH); ¹³C NMR (150.9

MHz, DMSO-d₄): d = 166.58, 148.18, 134.80, 131.69, 129.78,

128.78, 127.71, 113.43, 56.09; HRMS, m/z: 405.1807 ([M+H]⁺),

427.1629 ([M+Na]⁺); EA, C₂₄H₂₄N₂O₄: 404.4583, found (calcu-

lated) C: 71.60% (71.27%), H: 6.28% (5.98%), N: 7.13%

(6.93%).

N-(4-chloro-3-cyanobenzyl)benzamide (1f): white powder,

yield 35.9%. m. p.: 130.8-132.1 °C. IR (KBr):/cm^–1: u_C-Cl

=

1

694.23, u_C-C= 1287.69, u_C=O= 1527.86, u_CO-N= 1635.55; H

NMR (DMSO-d₆, 600 MHz), d (ppm): 4.867 (d, J = 6.0 Hz, 2H,

CH₂), 7.031 (s, 1H, PhH), 7.116 (d, J = 9.0 Hz, 1H, PhH), 7.463

(d, J = 8.4 Hz, 2H, PhH), 7.521 (t, J = 1.2 Hz, 1H, PhH), 7.905 (t, J

= 7.2 Hz, 3H, PhH), 9.037 (t, J = 5.9 Hz, 1H, NH); ¹³C NMR

(150.9 MHz, DMSO-d₄): d = 166.93, 134.41, 133.35, 131.88,

129.73, 129.05, 128.73, 127.88, 45.65; HRMS, m/z: 293.0689

([M+Na]⁺); EA, C₁₅H₁₁ClN₂O: 270.7136, found (calculated) C:

66.49% (66.55%), H: 4.53% (4.10%), N: 10.09% (10.35%).

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1f.

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1i.

N-(3-tert-butyl-2-hydroxy-5-methylbenzyl)benzamide

(2, 2’-bis-benzamide methyl)diphenyl methane (1j): white

powder, yield 64.4%. m. p.: 201.7-202.6 °C. IR (KBr):/cm^–1: u_C-C

= 694.26, u_CH2= 1528.03, u_CO-N= 1635.99; ¹H NMR (DMSO-d₆,

600 MHz), d (ppm): 3.933 (s, 4H, CH₂), 6.132 (d, J = 5.4 Hz, 4H,

PhH), 6.881 (t, J = 5.4 Hz, 2H, PhH), 7.093 (d, J = 3.0 Hz, 4H,

PhH), 7.230 (d, J = 7.2 Hz, 4H, PhH), 7.293 (t, J = 7.8 Hz, 2H,

PhH), 7.914 (t, J = 7.2 Hz, 4H, PhH), 9.047 (t, J = 5.4 Hz, 2H,

NH); ¹³C NMR (150.9 MHz, DMSO-d₄): d = 166.93, 134.42,

131.88, 128.73, 127.89, 45.65; HRMS, m/z: 457.1883 ([M+Na]⁺);

EA, C₂₉H₂₆N₂O₂: 434.5289, found (calculated) C: 80.58%

(80.16%%), H: 6.44% (6.03%), N: 6.66% (6.45%).

(1g): white crystal, yield 58.8%. m.p.: 162.5-163.4 °C. IR (KBr)

n/cm^–1: u_C-C= 735.72, u_CH3= 1549.48, u_CO-N= 1608.10, u_C-H

~

=

1

3082.78, u_OH= 3327.52; H NMR (DMSO-d₆, 600 MHz), d

(ppm): 1.347 (s, 9H, C(CH₃)), 2.186 (s, 3H, CH₃), 4.362 (d, J =

6.0 Hz, 2H, CH₂), 6.926 (d, J = 1.8 Hz, 2H, PhH), 7.502 (t, J = 7.8

Hz, 2H, PhH), 7.563 (s, 1H, PhH), 7.911 (d, J = 0.9 Hz, 2H, PhH),

9.489 (t, J = 5.9 Hz, 1H, NH), 9.573 (s, 1H, OH); ¹³C NMR (150.9

MHz, DMSO-d₄): d = 168.43, 151.99, 137.55, 133.30, 132.38,

129.13, 128.99, 127.86, 127.69, 127.11, 126.50, 34.88, 30.12,

20.99; HRMS, m/z: 298.1808 ([M+H]⁺), 320.1629 ([M+Na]⁺);

J. Chin. Chem. Soc. 2015, 62, 861-870

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867

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Wu et al.

¹H and ¹³C NMR data were consistent with the number and

388.4589, found (calculated) C: 74.01% (74.21%), H: 6.36%

(6.23%), N: 7.40% (7.21%).

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1m.

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1j.

N, N¢-[(5-formyl-2-hydroxy-1, 3-phenylene)bis(methy-

lene)]dibenzamide (1k): white powder, yield 41.2%. m. p.:

198.5-199.5 °C. IR (KBr):/cm^–1: u_C-C= 694.08, u_CO-H= 1527.46,

u_CO-N= 1634.68, u_OH= 3307.88; ¹H NMR (DMSO-d₆, 600 MHz),

d (ppm): 4.197 (s, 4H, CH₂), 5.879 (d, J = 5.4 Hz, 4H, PhH), 7.482

(t, J = 7.2 Hz, 2H, PhH), 7.526 (s, 2H, PhH), 7.553 (t, J = 7.2 Hz,

4H, PhH), 7.910 (t, J = 7.8 Hz, 2H, NH), 7.922 (s, 1H, OH), 9.046

(s, 1H, CHO); ¹³C NMR (150.9 MHz, DMSO-d₄): d = 166.93,

134.42, 131.88, 129.73, 129.04, 128.73, 127.89, 45.65; HRMS,

m/z: 411.1317 ([M+Na]⁺); EA, C₂₃H₂₀N₂O₄: 388.4159, found

(calculated) C: 70.96% (71.12%), H: 5.66% (5.19%), N: 7.75%

(7.21%).

Therefore, all characterization results were in agreement

with the proposed structures of the products. The results of spec-

trum are shown in the Supporting Information.

Quantum chemistry studies

To achieve better insights into the molecular structure of

BDCCs, quantum chemical analysis was performed using Gaus-

sian 3, a program that is routinely used to investigate chemical

structures, polymeric systems, and types of biological activity.

The most stable conformer for the compounds was fully geo-

metrical optimized by molecular orbital theory.²³Computational

studies for compound property prediction were performed by de-

termination of several parameters.

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1k.

Antimicrobial screening: The antimicrobial activity of the

synthesized compounds was tested against Staphylococcus

aureus (Sa; Gram-positive bacteria, ATCC 13565) and Esche-

richia coli (Ec; Gram-negative bacteria, ATCC 12435), both of

which were provided by the Laboratory of Microorganisms at the

Ocean University of China. The bacteria were cultivated in a bio-

chemical incubator and prepared for the experiments. Nutrient

agar was used as a medium.

N-(4-methoxy-5-methylbenzamide-2-methylbenzyl)benza

mide (1l): white powder, yield 50.3%. m. p.: 190.6-191.1 °C. IR

(KBr):/cm^–1: u_C-C= 692.98, u_CH3-O= 1256.34, u_CH3= 1547.69,

u_CO-N= 1642.04; ¹H NMR (DMSO-d₆, 600 MHz), d (ppm): 2.313

(s, 3H, CH₃), 3.805 (s, 3H, OCH₃), 4.397 (d, J = 6.0 Hz, 4H, CH₂),

6.822 (s, 1H, PhH), 7.145 (s, 1H, PhH), 7.396 (t, J = 8.4 Hz, 4H,

PhH), 7.496 (d, J = 8.4 Hz, 2H, PhH), 7.777 (d, J = 7.2 Hz, 4H,

PhH), 8.801 (t, J = 6.0 Hz, 2H, NH); ¹³C NMR (150.9 MHz,

DMSO-d₄): d = 166.83, 166.63, 155.68, 135.43, 135.06, 131.43,

129.21, 128.60, 127.67, 126.99, 124.54, 112.77, 55.92, 37.69,

19.29; HRMS, m/z: 389.1862([M+H]⁺), 411.1687 ([M+Na]⁺);

EA, C₂₄H₂₄N₂O₃: 388.4589, found (calculated) C: 74.15%

(74.21%), H: 6.34% (6.23%), N: 7.21% (7.21%).

Antibacterial activity test

Bacterial activation: Sa and Ec were respectively inocu-

lated on basal medium (peptone, 5.0 g; beef extract, 1.5 g; NaCl,

2.5 g; distilled water, 500 mL; pH = 7.2, 10 min of sterilization at

121 °C) kept in a refrigerator,²⁴activated for 24 h at 37 ± 1 °C. A

single bacterial colony was obtained from this culture. Bacteria

were scraped from the culture plate and resuspended in 5 mL of

liquid nutrient medium to obtain the desired final concentration of

10-fold serial dilutions.

¹H and ¹³C NMR data were consistent with the number and

location of hydrogen and carbon, and all spectroscopic data were

identical to the structure of the compound 1l.

N-(4-hydroxy-3-methylbenzamide-2, 5-dimethylbenzyl)

benzamide (1m): white crystal, yield 20.6%. m. p.: 201.2-202.1

Minimum inhibitory concentration (MIC) test for

determination of antimicrobial activity

°C. IR (KBr):/cm^–1: u_C-C= 710.48, u_CH3= 1303.70, u_CO-N

=

The resistance or sensitivity of a bacterial species can sim-

ply be assessed by direct comparison of its MIC with the concen-

trations of the agent that can be expected in the environment. In

this work, the 2-fold serial dilution method was used.²⁵First, 2

mL of nutrient fluid medium was added to test tubes using a pi-

pette. The initial concentration of each test compound was 1

mg/mL (solvent, acetone), doubling dilution in turns followed by

vortex mixing.²⁶Two control groups, one with the bacterial inoc-

ulate but without the tested compounds and a group without the

bacterial inoculate or tested compounds, were established. Exact

bacterial concentrations were obtained (105 cfu/mL; cfu, co-

1

1636.08, u_OH= 3264.21; H NMR (DMSO-d₆, 600 MHz), d

(ppm): 2.138 (s, 3H, CH₃), 2.370 (s, 3H, CH₃), 4.406 (d, J = 6.0

Hz, 2H, CH₂), 4.477 (d, J = 5.4 Hz, 2H, CH₂), 7.023 (s, 1H, PhH),

7.543 (d J = 5.4 Hz, 4H, PhH), 7.567 (t, J = 7.8 Hz, 1H, PhH),

7.913 (t, J = 7.8Hz, 4H, PhH), 8.716 (d, J = 7.2 Hz, 1H, PhH),

9.395 (t, J = 6.0 Hz, 2H, NH), 9.970 (s,1H, OH); ¹³C NMR (150.9

MHz, DMSO-d₄): d = 169.05, 166.33, 153.75, 134.93, 134.38,

133.42, 132.31, 131.55, 131.11, 128.86, 128.68, 128.28, 128.01,

127.77, 124.19, 122.71, 41.89, 37, 05, 16.84, 15.22; HRMS, m/z:

389.1863 ([M+H]⁺), 411.1684 ([M+Na]⁺); EA, C₂₄H₂₄N₂O₃:

868

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J. Chin. Chem. Soc. 2015, 62, 861-870

JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Capsaicin Derivatives: Calculation, Antifouling

lony-forming unit: colony formed on the agar plate after culti-

vation) by 10-fold dilution. Finally, Sa and Ec at the exponential

growth phase were incubated with increasing doses of each of the

thirteen tested compounds (range, 0–1 mg/mL) at 37 °C for 24 h

in liquid nutrient medium. An ultraviolet spectrophotometer was

used to determine the MIC of each compound.

Table 3. Composition of antifouling coatings (g)

Panel Acrylic Cuprous

Pigment Antifoulant Assistant Xylene

No.

resin

oxide

1343

1344

1345

1346

1347

1348

1349

1350

1351

1352

1353

1354

1355

1342

blank

55

0

25

0

17

0

1a

1b

1c

1d

1e

1f

2

0

11

0

All experimental procedures were completed in the purifi-

cation table, and each experiment was performed in triplicate.

During MIC determinations, the term inhibition refers to total

loss of ability to multiply.

1g

1h

1i

Agar diffusion method for antimicrobial activity

determination

1j

1k

1l

The agar diffusion method is used to determine what antibi-

otics/compounds, inhibit bacterial growth or alternatively are

bacteriostatic. The agar was soaked with a selected antibiotic/

chemical and then placed on a lawn of bacteria in a Petri dish. In-

hibition zones were measured around an Oxford cup to determine

whether or not the bacteria are resistant or susceptible to the se-

lected antibiotic/chemical. Sterilized medium with bacterial sus-

pension (105 cfu/ mL) was poured onto a Petri dish to a depth of

3–4 mm. An Oxford cup impregnated with the test compounds

(solvent, acetone) was placed on the solidified medium; this setup

was incubated at 37 °C for 24 h to study antibacterial and anti-

fungal activities. A group without the tested compounds was used

as a control.

1m

1n

1o

CONCLUSIONS

Thirteen new benzamide derivatives were success-

fully synthesized through Friedel-Crafts alkylation from

N-(hydroxylmethyl) benzamide and aromatic hydrocar-

bon-derived compounds. Three parameters, namely, De_L-H

,

HF values, and dipole, were also obtained by quantum

chemical calculation. The relationship between the three

parameters and properties such as activity, stability, and po-

larity was discussed. Results suggest that the orders of

De_L-Hand dipole are consistent with the antimicrobial and

antifouling performance of the resultant products. The anti-

bacterial activity of the BDCCs was evaluated by MIC and

bacteriostatic ring tests. The BDCCs were used as anti-

foulant coatings on panels to examine their antifouling per-

formance over four months in sea. The experimental results

demonstrated the excellent antifouling performance of all

BDCCs.

Antifouling properties of BDCCs: To develop new anti-

fouling paints, testing and quantifying the efficiency of new

antifoulants is crucial. However, all previously reported methods

are characterized by a lack of precise assessment of paint perfor-

mance.²⁷

Therefore, we considered the BDCCs as an auxiliary ma-

terial (antifoulant) added to commonly used antifouling paints.

The performance of the BDCCs in antifouling paints was ob-

served and compared with the performance of antifouling paint

without capsaicin derivatives and a blank according to GB

5370-85.²⁸

Therefore, compounds containing the active cap-

saicin structure present good application prospects in envi-

ronment-friendly antifouling coatings.

We polished and descaled PVC panels (900 mm ´ 300 mm

´ 3 mm) with sandpaper so that the antifouling paints adhere to

the substrate more easily and divided it into several parts.

Antifouling coatings containing the thirteen new compounds

were prepared according to Table 3 and then brushed three times

onto the panels, which were then fastened in air and dried. The

test panels were immersed in the waters of two ports in Qingdao,

China, to a depth of 1.5 m for a period of 120 d and inspected and

photographed at regular intervals. Thirteen new compounds and

two controls (i.e., paint without BDCCs and a blank) were

tested.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge financial support

by National Ocean Public Welfare Projects of China (No.

201005028-2), National Science and Technology Support

Program of China (No. 2012BAB15B02), and National

Natural Science Foundation of China (No. 50673085).

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Article Doi

Synthesis and Quantum Chemical Calculation of Benzamide Derivatives Containing Capsaicin and Their Bacteriostatic and Antifouling Properties

DOI: 10.1002/jccs.201500037

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